DISCUSSION
RA is a systemic autoimmune inflammatory disease that leads to painful
joint destruction and disability [11]. IVIG with good proven
beneficial and safety profile, is one of the first biological therapies
which was introduced already in 1981 by Imbach I et al, for immune
thrombocytopenic purpura (ITP) [11] . Since then, IVIG was employed
successfully in wide range of conditions such as immune deficiency,
sepsis, autoimmunity (e.g specific subgroups of RA patients, juvenile
chronic arthritis (JCA), Still’s disease, Guillain-Barré syndrome and
chronic inflammatory demyelinating polyneuropathy occurring in the
context of rheumatic disease, as well as in SLE, idiopathic inflammatory
myopathies, systemic sclerosis, and ANCA-associated vasculitides,
Still’s disease and more ) [13-24].
We show herein a beneficial effect of IVIG in the treatment in
established murine CIA. IVIG inhibited the arthritis clinical score,
inflammatory condition, exemplified by reduced the levels of circulating
inflammatory cytokines. IVIG prevent infiltration of immune cells by
histopathological examination inhibit joints destruction, as compared
with the untreated or PBS subjected CIA mice. The lower clinical score
was accompanied by reduced levels of anti-collagen antibodies
(P <0.001). Likewise, the diminished levels of
circulating inflammatory cytokines (IFNγ, IL-1β, IL-6, IL-17, TNFα) were
recorded, P <0.001. Our data support and strength our
previous observation that prophylactic treatment with IVIG inhibited the
severity of disease inflammation in murine CIA. In that study, IVIG
affinity purified on curillin peptides (ACPA-specific IVIG) and more
significantly citrullinated-peptides specific IVIG was found to be 200
times more efficient in the reduction of CIA inflammation activity,
inhibiting the inflammatory cytokines production ex-vivo by
spleen cells and enhanced expansion of spleen T regulatory cells as
compared to regular IVIG treatment [35]. Moreover , the
immunomodulatory makeup of IVIG in this study was attributed to its
anti-idiotypic activity via the Fab portion of the molecules,
although we can’t exclude the Fc contribution via elevation of T
regulatory cells number.
Lee SY et al, using a prophylactic protocol for the IVIG treatment in
CIA mice, showed that IVIG inhibited the development of disease score in
CIA mice, reduce the number of Th17 cells in the spleen, expansion of
spleen T-regulatory cells and inflammatory cytokines in the joints
[38] . Similarly, IVIG up-regulated IL-10 and Fcγ receptor IIB
expression by spleen cells (38). It is worth mentioning that in our
current study, IVIG was found to abrogate the course of disease, even
when the treatment started when the mice have already an arthritis score
of 2-3, as compared to the prophylactic treatment of (name of group)..
Passive transfer of sera from RA patients to K/BxN mice is an additional
murine model of arthritis [39]. IVIG given in a prophylactic
protocol or recombinant IgG1 Fc hexamer (Fc-μTP-L309C), resulted in
attenuation of arthritis score in the artherogenic K/BXN mice [40].
IVIG mode of action encompass numerous biological functions related in
part to the F(ab)2 of the molecule and/or to the Fc
activities. The anti-inflammatory activity of IVIG is based on the
following activities: a) Neutralization of inflammatory
cytokines since IVIG targets at least 13 different cytokines or
cytokine-inhibitors [41-45]. Due to the fact that IVIG has
anti-inflammatory cytokine activities, it was shown that IVIG is an
efficient therapy in the cytokine storm in cases of catastrophic
antiphospholipid syndrome, severe influenza, and also currently in
COVID-19 [43-48]. IVIG bind specifically the spike protein on
RS-Cov-2 as well as the receptor binding protein (personal data) ;b) IVIg impairs the generation of human monocyte-derived
anti-inflammatory macrophages by inducing JNK activation and activin ,
limiting the production of inflammatory macrophage differentiation by
inhibiting GM-CSF-driven STAT5 activation in-vitro [49].c) IVIG can function through the Fc portion thus contributing
to the expansion of T regulatory cells , Fc receptor blocking including
the sialic acid content of the Fc portion of the antibodies and the
interaction with ITAM-bearing Fc receptors [50,51]. Of note, and as
opposed to some common assumptions in the medical scientific community,
IVIG was found to have less side effects as compared to current
biological treatments which might cause severe side effect and loss of
efficacy in the long-term. Moreover, IVIG might be even cheaper than
current expansive biological agents, therefore it might change the
financial burden of biological treatment in RA and other
inflammatory/autoimmune diseases.